University of Massachusetts Medical School Faculty Publications
UMMS Affiliation
Department of Orthopedics and Physical Rehabilitation; Program in Molecular Medicine; Diabetes Center of Excellence; School of Medicine
Publication Date
2017-03-11
Document Type
Article
Disciplines
Cell Biology | Endocrinology, Diabetes, and Metabolism | Orthopedics
Abstract
BACKGROUND: Poor bone quality, increased fracture risks, and impaired bone healing are orthopedic comorbidities of type 1 diabetes (T1DM). Standard osteogenic growth factor treatments are inadequate in fully rescuing retarded healing of traumatic T1DM long bone injuries where both periosteal and bone marrow niches are disrupted. We test the hypotheses that osteogenesis of bone marrow-derived stromal cells (BMSCs) and periosteum-derived cells (PDCs), two critical skeletal progenitors in long bone healing, are both impaired in T1DM and that they respond differentially to osteogenic bone morphogenetic proteins (BMPs) and/or insulin-like growth factor-1 (IGF-1) rescue.
METHODS: BMSCs and PDCs were isolated from Biobreeding Diabetes Prone/Worcester rats acquiring T1DM and normal Wistar rats. Proliferation, osteogenesis, and adipogenesis of the diabetic progenitors were compared with normal controls. Responses of diabetic progenitors to osteogenesis rescue by rhBMP-2/7 heterodimer (45 or 300 ng/ml) and/or rhIGF-1 (15 or 100 ng/ml) in normal and high glucose cultures were examined by alizarin red staining and qPCR.
RESULTS: Diabetic BMSCs and PDCs proliferated slower and underwent poorer osteogenesis than nondiabetic controls, and these impairments were exacerbated in high glucose cultures. Osteogenesis of diabetic PDCs was rescued by rhBMP-2/7 or rhBMP-2/7 + rhIGF-1 in both normal and high glucose cultures in a dose-dependent manner. Diabetic BMSCs, however, only responded to 300 ng/nl rhBMP-2/7 with/without 100 ng/ml rhIGF-1 in normal but not high glucose osteogenic culture. IGF-1 alone was insufficient in rescuing the osteogenesis of either diabetic progenitor. Supplementing rhBMP-2/7 in high glucose osteogenic culture significantly enhanced gene expressions of type 1 collagen (Col 1), osteocalcin (OCN), and glucose transporter 1 (GLUT1) while suppressing that of adipogenic marker peroxisome proliferator-activated receptor gamma (PPARgamma) in diabetic PDCs. The same treatment in high glucose culture only resulted in a moderate increase in Col 1, but no significant changes in OCN or GLUT1 expressions in diabetic BMSCs.
CONCLUSIONS: This study demonstrates more effective osteogenesis rescue of diabetic PDCs than BMSCs by rhBMP-2/7 with/without rhIGF-1 in a hyperglycemia environment, underscoring the necessity to tailor biochemical therapeutics to specific skeletal progenitor niches. Our data also suggest potential benefits of combining growth factor treatment with blood glucose management to optimize orthopedic therapeutic outcomes for T1DM patients.
Keywords
bone marrow-derived stromal cell, bone morphogenetic protein-2/7 heterodimer, growth factor rescue, hyperglycemia, insulin-like growth factor-1, osteogenesis, periosteum-derived cell, type 1 diabetes
Rights and Permissions
© The Author(s). 2017.
DOI of Published Version
10.1186/s13287-017-0521-6
Source
Stem Cell Res Ther. 2017 Mar 11;8(1):65. doi: 10.1186/s13287-017-0521-6. Link to article on publisher's site
Related Resources
Journal/Book/Conference Title
Stem cell research and therapy
PubMed ID
28283030
Repository Citation
Filion TM, Skelly JD, Huang H, Greiner DL, Ayers DC, Song J. (2017). Impaired osteogenesis of T1DM bone marrow-derived stromal cells and periosteum-derived cells and their differential in-vitro responses to growth factor rescue. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1186/s13287-017-0521-6. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1373
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Cell Biology Commons, Endocrinology, Diabetes, and Metabolism Commons, Orthopedics Commons